1Introduction

The purpose of toxicity testing is to generate information about a substance’s toxic properties so that the health and environmental risks it poses can be adequately evaluated. Federal agencies use information from toxicity testing to establish acceptable concentrations of environmental agents in drinking water, to set permissible exposure limits for workers, to establish tolerances for pesticide residues on food, to register and re-register pesticides, and ultimately to protect public health and the environment. As reflected in new directives and initiatives for toxicity testing in the United States and Europe, the demand for toxicity information to provide a rational basis for regulating environmental agents has increased. At the same time, testing technologies and methods have continued to emerge. Thus, the U.S. Environmental Protection Agency (EPA) recognized the need for a comprehensive review of established and emerging toxicity-testing methods and strategies and asked the National Research Council (NRC) to conduct such a review and to develop a long-range vision and strategy for toxicity testing. In response to EPA’s request, the NRC convened the Committee on Toxicity Testing and Assessment of Environmental Agents, which prepared this report.

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Toxicity Testing for Assessment of Environmental Agents: Interim Report
1
Introduction
The purpose of toxicity testing is to generate information about a substance’s toxic properties so that the health and environmental risks it poses can be adequately evaluated. Federal agencies use information from toxicity testing to establish acceptable concentrations of environmental agents in drinking water, to set permissible exposure limits for workers, to establish tolerances for pesticide residues on food, to register and re-register pesticides, and ultimately to protect public health and the environment. As reflected in new directives and initiatives for toxicity testing in the United States and Europe, the demand for toxicity information to provide a rational basis for regulating environmental agents has increased. At the same time, testing technologies and methods have continued to emerge. Thus, the U.S. Environmental Protection Agency (EPA) recognized the need for a comprehensive review of established and emerging toxicity-testing methods and strategies and asked the National Research Council (NRC) to conduct such a review and to develop a long-range vision and strategy for toxicity testing. In response to EPA’s request, the NRC convened the Committee on Toxicity Testing and Assessment of Environmental Agents, which prepared this report.

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REGULATORY REQUIREMENTS
The U.S. Congress has enacted laws calling for limits on chemical exposures that “provide an ample margin of safety to protect public health” (Clean Air Act; 42 USC §7412(f) [2003]), “assure protection of public health” (Clean Water Act; 33 USC §1312(a) [2003]), provide “a reasonable certainty that no harm will result” (Food Quality Protection Act; 21 USC §346a(b) [2003]), and “adequately assures, to the extent feasible, on the basis of the best available evidence, that no employee will suffer material impairment of health or functional capacity” (Occupational Safety and Health Act; 29 USC §655(b) [2003]) (see Table 1-1). Federal agencies implement those statutes by promulgating standards or adopting guidance levels—such as air-quality criteria, maximum contaminant levels for drinking water, pesticide-residue tolerances, and permissible exposure limits for workplaces—that limit people’s exposure to chemicals. The standards and guidance levels are often developed through human health risk assessment, although other factors—such as treatment technology, feasibility, benefits, and costs—may also be considered. Toxicity testing in laboratory animals provides much of the information needed to characterize the nature and extent of the risk so that appropriate risk-management action can be taken.
TOXICITY TESTING
Many factors are determinants of health, including socioeconomic status, birth weight, sex, genetics, diet, pathogens, smoking habits, cultural activities, and the environment. Exposures to environmental agents contribute to the aggregate effects of the other factors, but the nature and magnitude of the contribution are often debated. The results of toxicity testing can help to clarify risks to health posed by environmental exposures and provide support for effective risk-management decisions.
Toxicity-testing requirements to evaluate effects on human health often involve studies of whole animals, typically rats, mice, dogs, and rabbits, although other species, including humans, can be used. Exposures can range from short-term (for example, an hour) to long-term (for example, 2 years) and be continuous or episodic or consist of a single event. Tests may focus on a particular life stage, sex, or condition of exposure. The effects evaluated can be numerous and can include such diverse outcomes as subtle behavioral changes, impairment of reproduc-

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tion, abnormal development, alterations in gene function, organ toxicity, cancer, and death. New methods that rely on molecular biology, information technology, and alternatives to whole-animal testing are emerging and may provide information that allows better extrapolation of results in test species to the genetically diverse human population. Some new methods may eventually replace various traditional toxicity tests.
Federal agencies and international organizations—including EPA, the National Toxicology Program (NTP) (Chhabra et al. 1990), the Food and Drug Administration (FDA 1997, 2004), and the Organisation for Economic Co-operation and Development (OECD 2004, 2005)—have developed documents that provide guidance on testing protocols. Testing guidelines are intended to convey to members of the regulated community what is expected of them and provide a uniform and sometimes flexible approach to toxicity testing that produces comparable results. The OECD protocols serve not only as standards but as means to harmonize requirements among regulatory authorities and thus reduce repetition of studies. The harmonization efforts should increase efficiency and reduce animal use.
CHALLENGES TO TOXICITY TESTING AND ASSESSMENT
The continuing challenge is to determine the best methods for extrapolating from the exposure conditions and effects observed in the laboratory to those relevant to the human environment. Toxicity-testing data can be used in various ways to aid in that extrapolation. Pharmacokinetic data can provide a better understanding of the qualitative and quantitative comparability of the relationship between exposure and dose in test species and in humans. Population-based studies that examine effects on exposed humans can provide information that improves extrapolation from laboratory-animal data to humans or in some cases eliminates the need to rely on laboratory-animal data altogether. Studies that provide a quantitative understanding of the difference in susceptibility to a chemical between humans and test species can be used to develop an interspecies adjustment factor based on scientific data rather than science policy. Finally, studies that provide an understanding of variations in susceptibility to the effects of a substance in different populations or life stages can help to identify substances that require special regulatory attention to protect sensitive groups and may also identify exposures that will have no deleterious effects even in sensitive people.

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Studies like those discussed have resulted in much-improved human risk estimation, but substantial challenges remain. Most toxicity tests use exposures that exceed environmental exposures by several orders of magnitude to improve test sensitivity, but high exposures can distort the specificity of a test and its qualitative and quantitative applicability to actual human exposure. Scientific developments and new test methods are needed to address people’s multiple simultaneous chemical exposures, their potential interactions, and the many factors that affect people’s susceptibility to chemical exposures. Thus, even extensive testing and an accurate understanding of biologic modes of action cannot predict exactly what will happen in a diverse human population under environmental conditions of exposure. Precise descriptions of risk are desirable to protect public health, but they remain elusive. Nevertheless, even with these challenges and uncertainties, toxicity-testing data provide critical information for assessing hazard and risk potential and will continue to play a critical role in rational decision-making.
As noted above, EPA and other federal agencies have statutory responsibilities for obtaining and evaluating animal and human toxicity data for regulatory decision-making purposes. The numbers of health outcomes and questions that must be considered have also grown over the years. EPA and others have responded to the increased need to address various outcomes by developing risk-assessment guidelines and testing requirements, such as the risk-assessment guidelines for neurotoxicity (IPCS 2001; OECD 2004; EPA 1998), guidelines on children’s cancer risk (EPA 2005), testing guidelines for developmental neurotoxicity (OECD 2004; EPA 1998) and guidelines for the use of genomics data (EPA 2004). Still, there is a growing recognition that because traditional toxicity testing approaches are time consuming and resource intensive, a large volume of existing and newly introduced chemicals cannot be adequately assessed using current testing practices. EPA recognized the need to review traditional toxicity testing approaches, new data-generation methods, and testing strategies comprehensively and asked NRC to perform such a review.
COMMITTEE’S TASK AND APPROACH
The committee members were selected for their expertise in developmental toxicology, reproductive toxicology, neurotoxicology, immunology, pediatrics and neonatology, epidemiology, biostatistics, in vitro

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methods and models, molecular biology, pharmacology, physiologically based pharmacokinetic and pharmacodynamic models, genetics, toxicogenomics, cancer hazard assessment, and risk assessment.
The committee was asked to conduct a two-part study to assess and advance current approaches to toxicity testing and assessment undertaken to meet regulatory data needs. For the first part of the study, the committee was asked to review selected aspects of several relevant reports by EPA and others. Those reports included EPA’s 2002 review of the reference-dose and reference-concentration processes (EPA 2002), the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) work to develop a tiered toxicity-testing approach for agricultural-chemical safety evaluations (ILSI-HESI 2004a,b,c), the work of the Interagency Coordinating Committee on the Validation of Alternative Methods to develop and validate alternatives to animal testing (ICCVAM 1997), pertinent NRC reports, and current work of NRC standing committees. Those reports were to be evaluated for specific elements, including analysis of current and anticipated regulatory needs, discussion of the current and planned inventory of toxicity-testing and assessment schemes and methods, evaluation of potential uses and limitations of new or alternative testing methods and analysis of how they might influence or define future testing strategies, and discussion of scientific advances that could affect the nature of information needed to assess potential human toxicity more completely. The present report was prepared to fulfill the first part of the study.
For the second part of the study, the committee was asked to build on the work presented in this report and develop a long-range vision and strategic plan to advance the practices of toxicity testing and human health assessment of environmental contaminants. The second report is expected to be completed by fall 2006.
To accomplish the task of preparing its first report, the committee held four meetings. The first three, held from June 2004 to November 2004, included public sessions. At the public sessions, the committee heard presentations from staff of several EPA offices, including representatives from the Office of Research and Development, the Office of Pesticide Programs, the Office of Children’s Health, the National Health and Environmental Effects Research Laboratory, and the National Center for Environmental Assessment. The committee also heard presentations from staff of other federal agencies and organizations, including the NTP, the FDA Center for Drug Evaluation and Research and Center for Food Safety and Applied Nutrition, the European Center for the Valida-

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tion of Alternative Methods, and the ILSI HESI and Risk Sciences Institute. The committee considered numerous documents, including those mentioned in the statement of task but also others, such as FDA guidance on pharmacogenomic-data submissions (FDA 2005) and the NTP Roadmap for the Future (NTP 2004).
ORGANIZATION OF THE REPORT
In Chapter 2, the committee presents an overview of consensus-study protocols focusing primarily on EPA guidelines. The objective of that chapter is not to detail each type of testing protocol but rather to indicate the general types of whole-animal and in vitro toxicity testing now in use. Chapter 3 considers a variety of human-based studies ranging from clinical trials to epidemiologic studies. Challenges that have often prevented the use of epidemiologic studies in regulatory risk assessment and possible advances and improvements in epidemiology are discussed. Chapter 4 examines applications of toxicity tests in testing strategies that are used to rank, screen, or characterize chemical toxicity. Several examples of testing strategies are presented. The strategies identified are not meant to be exhaustive but to illustrate the array of toxicity tests that may be required under different circumstances. Chapter 5 provides an overview of risk-assessment guideline documents that deal with the use of toxicity data in human health risk assessment and concludes with observations regarding strengths and weaknesses of the current system for generating toxicologic data to assess environmental risks. Chapter 6 is the committee’s assessment of the various, and often conflicting, demands on the regulatory toxicity-testing framework and a review of near-term and long-term approaches that hold promise for improving toxicity testing. The chapter includes comments on the portion of the EPA review of its reference-dose and reference-concentration process that is relevant to toxicity testing and comments on the proposed ILSI-HESI approaches for pesticides, the NTP Roadmap for the Future, and the European Union’s program. Chapter 7 discusses alternatives to animal testing and a few emerging technologies, such as -omics approaches and computational toxicology. It concludes with a discussion of validation to emphasize the importance of evaluating new toxicity-testing methods to ensure that the information obtained from them is at least as good as, if not better than, conventional mammalian models.

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